Acute upper gastrointestinal bleeding due to portal hypertension in a patient with primary myelofibrosis:A case report

BACKGROUND Acute upper gastrointestinal bleeding is a common medical emergency that has a 10%hospital mortality rate.According to the etiology,this disease can be divided into acute varicose veins and nonvaricose veins.Bleeding from esophageal varices is a life-threatening complication of portal hypertension.Portal hypertension is a clinical syndrome defined as a portal venous pressure that exceeds 10 mmHg.Cirrhosis is the most common cause of portal hypertension,and thrombosis of the portal system not associated with liver cirrhosis is the second most common cause of portal hypertension in the Western world.Primary myeloproliferative disorders are the main cause of portal venous thrombosis,and somatic mutations in the Janus kinase 2 gene(JAK2 V617F)can be found in approximately 90% of polycythemia vera,50% of essential thrombocyrosis and 50% of primary myelofibrosis.CASE SUMMARY We present a rare case of primary myelofibrosis with gastrointestinal bleeding as the primary manifestation that presented as portal-superior-splenic mesenteric vein thrombosis.Peripheral blood tests revealed the presence of the JAK2 V617F mutation.Bone marrow biopsy ultimately confirmed the diagnosis of myelofibrosis(MF-2 grade).CONCLUSION In patients with acute esophageal variceal bleeding due to portal hypertension and vein thrombosis without cirrhosis,the possibility of myeloproliferative neoplasms should be considered,and the JAK2 mutation test should be performed.

奥亚膨胀度与G、Y、MF、Vdaf关系及测定中常见问题剖析

奥阿膨胀度是以膨胀度(b)和收缩度(a)等参数表征烟煤膨胀性和塑性的指标,该方法不仅能反映胶质体的量,而且还能计算胶质体质量,可与胶质层最大厚度 Y共同表征其粘结特性,是一种较好的分级方法。在鉴别胶质煤炭上,与其它各项指数相比,有明显的优越性。其与煤的岩石相成分联系密切,被应用于研究煤的成焦机理,评价煤的质量,分级,以及对配煤、焦化以及焦的强度预报等等。

稳态随机先验下MF-VAR预测模型及其应用

准确把握宏观经济发展趋势有利于前瞻性地调控经济运行,防范外部冲击。当前广泛用于宏观经济预测的MF-VAR模型,虽然能胜任常态情形的预测任务,但其参数估计过程多以传统Minnesota形式分布作为推断先验,难以贴合现实中异方差性的非理想预测环境。文章引入稳态随机先验对模型进行改进和优化,并通过湖北省主要宏观经济指标进行实例验证,发现稳态先验的“均值调整”信念驱使预测向均值回归,在简化估计程序的同时还能提高远期视野下的预测精度;随机先验的时变方差设定能有效捕捉序列的结构变动,使模型能同时适应常态和不确定性冲击的情形;分级稳态和因子随机波动可以牺牲部分样本信息而兼顾降维能力与计算优势。稳态随机先验的延展性和灵活性拓展了MF-VAR模型的应用场景,放宽了模型的应用条件,并进一步提高了预测精度。

Pseudohyperkalemia with Myelofibrosis after Splenectomy

SEUDOHYPERKALEMIA refers the serum potassiumlevel is higher than plasma potassium due tovarious reasons in vitro monitoring, but actualpotassium level in vivo is at the normal range. Aseries of inappropriate clinical interventions due to initialfailure to recognize it may actually decrease potassiumlevel，which could cause life-threatening condition. Here wereport a patient with myelofibrosis who occurred spurioushyperkalemia after splenectomy, aiming at emphasizingthe importance of recognizing pseudodyperkalemia.

Peritonitis in myelofibrosis:a cautionary tale

BACKGROUND: Primary myelofibrosis (PMF) is a myeloproliferative disorder characterized by bone marrow fibrosis. Extra-medullary hematopoiesis sometimes occurs even in the peritoneal cavity, apart from organs such as the liver, spleen, and lymph nodes. This may sometimes be complicated by spontaneous infection and complications. We report a rather unusual case of PMF, who presented as an emergency with spontaneous peritonitis to general surgery department and had a fulminant clinical course. METHOD: A clinical case note review was done and a literature search was undertaken. RESULTS: A rather unusual case of PMF, who presented as an emergency with spontaneous peritonitis to general surgery department. The patient underwent a laparotomy and had a fulminant clinical course. CONCLUSIONS: Peritonitis in myelofibrosis may have a number of causes. Clinicians need to be aware of them and provide conservative management prior to surgical treatment. (Hepatobiliary Pancreat Dis Int 2010; 9: 651-653)

JAK2 V617F, MPL W515L and JAK2 Exon 12 Mutations in Chinese Patients with Primary Myelofibrosis

Objective： JAK2 V617F, MPL W515L and JAK2 exon 12 mutations are novel acquired mutations that induce constitutive cytokine-independent activation of the JAK-STAT pathway in myeloproliferative disorders （MPD）. The discovery of these mutations provides novel mechanism for activation of signal transduction in hematopoietic malignancies. This research was to investigate their prevalence in Chinese patients with primary myelofibrosis （PMF）. Methods： We introduced allele-specific PCR （AS-PCR） combined with sequence analysis to simultaneously screen JAK2 V617F, MPL W515L and JAK2 exon 12 mutations in 30 patients with PMF. Results： Fifteen PMF patients （50.0%） carried JAK2 V617F mutation, and only two JAK2 V617F-negative patients （6.7%） harbored MPL W515L mutation. None had JAK2 exon 12 mutations. Furthermore, these three mutations were not detected in 50 healthy controls. Conclusion： MPL W515L and JAK2 V617F mutations existed in PMF patients but JAK2 exon 12 mutations not. JAK2 V617F and MPL W515L and mutations might contribute to the primary molecular pathogenesis in patients with PMF.

Portal hypertension secondary to myelofibrosis with myeloid metaplasia:A study of 13 cases

AIM:To describe the clinical presentation and complications of portal hypertension (PH) secondary to myelofibrosis with myeloid metaplasia (MMM).METHODS: Medical records for 123 patients with MMM were reviewed.RESULTS: Thirteen patients with PH secondary to MMM were identified. Median ages at time of MMM and PH diagnosis were 61 and 66 years, respectively. The interval from MMM diagnosis to presentation with one of the PH features ranged from 1 to 11 years. Variceal bleeding and ascites were the most common presentations. Of the eight patients who presented with variceal bleeding, six patients underwent endoscopic variceal ligation (EVL) with no variceal recurrence or hematological worsening during a 12-mo follow up period.CONCLUSION: Patients with MMM might develop PH. Exact mechanisms leading to PH in MMM are still controversial. As in other etiologies, variceal bleeding and ascites are the most common presentations. Anemia may correlate with, and/or predict, the severity of the PH presentation in these patients. EVL can successfully control variceal bleeding in MMM. Further clinical studies are required.

Multiple esophageal variceal ruptures with massive ascites due to myelofibrosis-induced portal hypertension

A 75-year old man had been diagnosed at 42 years of age as having polycythemia vera and had been monitored at another hospital. Progression of anemia had been recognized at about age 70 years, and the patient was thus referred to our center in 2008 where secondary myelofibrosis was diagnosed based on bone marrow biopsy findings. Hematemesis due to rupture of esophageal varices occurred in January and February of 2011. The bleeding was stopped by endoscopic variceal ligation. Furthermore, in March of the same year, hematemesis recurred and the patient was transported to our center. He was in irreversible hemorrhagic shock and died. The autopsy showed severe bone marrow fibrosis with mainly argyrophilic fibers, an observation consistent with myelofibrosis. The liver weighed 1856 g the spleen 1572 g, indicating marked hepatosplenomegaly. The liver and spleen both showed extramedullary hemopoiesis. Myelofibrosis is often complicated by portal hypertension and is occasionally associated with gastrointestinal hemorrhage due to esophageal varices. A patient diagnosed as having myelofibrosis needs to be screened for esophageal/gastric varices. Myelofibrosis has a poor prognosis. Therefore, it is necessary to carefully decide the therapeutic strategy in consideration of the patient's concomitant conditions, treatment invasiveness and quality of life.

Primary myelofibrosis with concurrent CALR and MPL mutations:A case report

BACKGROUND Primary myelofibrosis(PMF)is a myeloproliferative neoplasm(MPN)characterized by recurrent mutations in the JAK2,CALR,and MPL genes.The CALR and MPL co-mutation is very rare.To our knowledge,no more than five cases have been reported.Here,we report a case of PMF in which a CALR and MPL co-mutation was detected by next-generation sequencing(NGS)technology,and a literature review was performed.CASE SUMMARY A 73-year-old woman was admitted to our hospital in 2018 due to abdominal distension.The patient had splenomegaly,lymphadenopathy,leukopenia,anemia,and immature granulocytes in peripheral blood.There were dacrocytes and atypical megakaryocytes in bone marrow,and megakaryocytic proliferation was very active,accompanied by reticulin fibrosis grade 2.By NGS analysis of the bone marrow sample,we detected mutations in CALR,MPL,and PIK3RI,while JAK2 V617F and BCR-ABL were negative.Therefore,the patient was diagnosed with PMF and received oral ruxolitinib.However,the spleen and hematologic responses were poor.We review the literature,analyze previous reports of the mutation sites in our patient and differences between our patient and other reported cases of co-mutated CALR and MPL genes,and discuss the reason why the CALR and MPL co-mutations are rare and possible mechanisms and their impact on the prognosis of patients.CONCLUSION CALR and MPL mutations can be concurrent in MPN,but they are rare.The use of NGS may help to identify more patients with co-mutated CALR and MPL genes.This will help to further explore the mechanism and its impact on these patients to develop appropriate treatment strategies.

Intestinal obstruction caused by extramedullary hematopoiesis and ascites in primary myelofibrosis

Primary myelofibrosis(PMF) is a clonal hematopoietic stem cell disorder. It is characterized by bone marrow fibrosis, extramedullary hematopoiesis with hepatosplenomegaly and leukoerythroblastosis in the peripheral blood. The main clinical manifestations of PMF are anemia, bleeding, hepatosplenomegaly, fatigue, and fever. Here we report a rare case of PMF with anemia, small bowel obstruction and ascites due to extramedullary hematopoiesis and portal hypertension. The diagnosis was difficult to establish before surgery and the differential diagnosis is discussed.

Acute Panmyelosis with Myelofibrosis: A Rare Subtype of Acute Myeloid Leukemia

Acute panmyelosis with myelofibrosis (APMF) is a subtype of acute myeloid leukemia (AML) classified among the category of “AML, not otherwise specified” in the WHO 2016 classification of hematopoietic tumors. It is a rare, fatal hematological neoplasm that is characterized by acute onset of cytopenias and bone marrow fibrosis in the absence of splenomegaly or fibrosis related morphological changes in the red blood cells. The difficulty of diagnosis and management explains why APMF is rarely reported in Africa. We report here the case of a 30-year-old man who presented with dizziness, palpitations and dyspnea. Diagnosis of APMF was retained on bone marrow histology and immunohistochemistry which showed bone marrow fibrosis and high cellularity with majority of myeloid blast cells. The patient was treated by low dose cytarabine monotherapy 30 mg/m2 per week. At 3 months of treatment, the patient was transfusion-independent, with normalization of hemoglobin and platelets counts. However, the death occurred after 8 months. This case highlights the diagnosis specificity and management of AMPF, knowing the number of potential differential diagnoses and difficulties of its therapeutic management.

在有与 myelofibrosis 复杂的类型 2 糖尿病的一个病人的 Hyperinsulinemia 和胰岛素电阻

Inflammation induces insulin resistance and hyperinsulinemia due to elevation of serum cytokines such as tumor necrosis factor-α and interleukins. Chronic myeloproliferative diseases including myelofibrosis show higher serum interleukin levels than healthy subjects, which has been suggested to be the useful markers for disease activity. However, an association between myelofibrosis and insulin resistance has not ever been discussed anywhere. Here we report a case of type 2 diabetes showing remarkable hyperinsulinemia and insulin resistance possibly due to myelofibrosis.

基于分子动力学模拟的扩展青霉棒曲霉素MFS蛋白转运机制研究

扩展青霉可产生具有毒性的次生代谢产物—棒曲霉素。PatC基因编码MFS转运蛋白将棒曲霉素的前体物质转运至胞外,在棒曲霉素防治中具有较高的参考价值。为研究PatC蛋白的转运机制,利用生物信息学方法预测PatC的空间结构,采用分子对接和分子动力学模拟解析棒曲霉素前体分子(E-ascladiol)与PatC的作用位点及可能的作用机制。结果表明,该蛋白含有546个氨基酸,含有14个跨膜螺旋且具有MFS功能结构域;分子对接结果显示,该蛋白与E-ascladiol存在4个结合位点,分别为SER353、TYR336、PRO339、PRO188。针对Wild蛋白复合体系及P188A突变体系进行200 ns的分子动力学模拟,结果显示小分子底物与PatC结合紧密,且位于氨基酸序列Pro188~Ser197aa和Gly231~Val241aa区域内形成复合体后,蛋白的柔性发生强烈变化,由此可推测这两个区域可能存在作用位点。通过对P188A突变体系的各参数数据的分析,可以预测PRO188作为PatC的重要靶点,为后续的分子实验提供基础理论。该研究结果为探索棒曲霉素的转运机制奠定基础,为防治苹果腐烂提供了新策略。

Advances in the Study of High-Risk Gene Mutations for Primary Myelofibrosis

Primary myelofibrosis is a kind of MPNs due to clonal appreciation of hematopoietic stem cells. With the development of second-generation sequencing, high-risk mutation (HMR) genes such as ASXL1, EZH2, SRSF2, and IDH1/2 have been shown to be associated with disease prognosis and progression, and although allo-HSCT remains the only possible treatment for PMF, with the development of JAK inhibitors, there is an increasing interest in the study of inhibitors of these mutant loci.

Myelofibrosis: Prognostication and cytoreductive treatment

Myeloproliferative neoplasms include three diseases: polycythemia vera, essential thrombocythemia and primary myelofibrosis(PMF), currently diagnosed according to the 2008 World Health Organization criteria. Patients with PMF may encounter many complications, and, among these, disease progression is the most severe. Concerning prognostication of Myelofibrosis(MF), the International Prognostic scoring system(IPSS)(International Prognostic Scoring System) model at diagnosis and the Dynamic IPSS(DIPSS) anytime during the course of the disease may be useful to define survival of MF patients. The IPSS and the DIPSS are based on age greater than 65 years, presence of constitutional symptoms, hemoglobin level less than 10 g/d L, leukocyte count greater than 25 × 109/L, and circulating blast cells 1% or greater. Cytogenetic profile and mutational analysis seem to be the next step to implement MF prognostication. Concerning treatments, hydroxyurea has been considered until now the drug of choice when an anti-myeloproliferative effect is needed, but recent data on JAK inhibitors demonstrated a significant effect of these drugs on splenomegaly and symptoms.

Leukocytosis at Diagnosis in Patients with Essential Thrombocythemia Is a Risk Factor for Transformation into Myelofibrosis

Myelofibrosis (MF) represents the major long-term complication of essential thrombocythemia (ET). There is evidence that leukocytosis at diagnosis is associated with poorer survival in patients with ET. In this study, we retrospectively evaluated 143 patients with ET, diagnosed in agreement with WHO criteria, followed in a single centre over >10 years. Nine of them transformed into MF (post-essential thrombocythemia-myelofibrosis PET-MF). We compared PET-MF data at diagnosis with that of the remaining 134 patients (ET-1) and with a selected sub-group of ET-1 (ET-2, 19 pats) sex, age and follow-up duration matched to PET-MF. The PET-MF evolution rate was 4.6 per 1000 person-years;white blood cells count (WBC) count, haemoglobin levels and hematocrit were higher in PET-MF than in ET-1 (P = 0.01) while only WBC was higher than in ET-2 (P = 0.01). With multivariate analysis, only WBC count retained its signifi-cance. Our study highlights the prognostic relevance of leukocytosis on myelofibrotic transformation of ET.

Primary myelofibrosis with thrombophilia as first symptom combined with thalassemia and Gilbert syndrome:A case report

BACKGROUND A 46-year-old Han man first had sigmoid sinus and transverse sinus venous thrombosis at the age of 42.At the age of 44,he once again developed thrombosis.Genetic testing showed heterozygous SERPINC1 mutation,bone marrow biopsy showed fibrosis grade 1(MF-1),and JAK2 V617F mutation was positive,accompanied by UGT1A1 mutation andβ-thalassemia gene mutation.CASE SUMMARY A 46-year-old Han man was first found to have sigmoid sinus and transverse sinus venous thrombosis at the age of 42 but had no individual or family thrombosis history,and he had been regularly taking warfarin anticoagulant therapy for a long period of time.At the age of 44,venous thrombosis reappeared in parts of the intrahepatic vein,main portal vein,splenic vein,and superior mesenteric vein,and his spleen was obviously enlarged.He had a history of jaundice for many years,and genetic testing revealed that he carried a heterozygous SERPINC1 mutation.Bone marrow biopsy showed multifocal fibrous tissue hyperplasia among trabeculae and focal fibrosis.He was positive for the JAK2 V617F mutation.At the same time,UGT1A1 andβ-thalassemia gene mutations existed,and a SERPINC1 mutation and UGT1A1 mutation were both found in his parents.CONCLUSION The patient in this case had thrombophilia as the primary symptom,JAK2V617-positive myeloproliferative neoplasm(MPN)was the main potential cause,and hereditary AT-III deficiency may have been one of multiple secondary causes.It remains to be determined whether UGT1A1 andβ-thalassemia gene mutations are related to thrombophilia.However,the clinical features of MPN in this patient were hidden,and the relevant clinical features of coexisting thalassemia and hereditary Gilbert syndrome,reported here for the first time domestically and abroad,were complicating factors,causing great difficulties for a clear diagnosis.Thus,when thrombophilia has been determined,it is necessary to screen the relevant latent problems overall.When the clinical features cannot be perfectly explained by one etiology,a relevant comprehensive examination should also be initiated from the perspective of multiple etiologies.

Turner syndrome with primary myelofibrosis,cirrhosis and ovarian cystic mass:A case report

BACKGROUND Turner syndrome(TS)with leukemia is a complicated clinical condition.The clinical course and outcome of these patients are poor,so the treatment and prognosis of TS with hematological malignancies deserve our attention.CASE SUMMARY Here,we report a case of a 20-year-old woman diagnosed with TS,primary myelofibrosis(PMF),cirrhosis,and an ovarian cystic mass.This is the first report on the coexistence of TS and PMF with the MPL and SH2B3 mutations.The patient was diagnosed with cirrhosis of unknown cause,splenomegaly and severe gastroesophageal varices.Additionally,an ovarian cystic mass caused the patient to appear pregnant.The patient was treated with the JAK2 inhibitor-ruxolitinib according to peripheral blood cells,although myelofibrosis was improved,the splenomegaly did not reduce.Moreover,hematemesis and melena occasionally occurred.CONCLUSION Ruxolitinib may clearly reduce splenomegaly.Though myelofibrosis was improved,cirrhosis and splenomegaly in this case continued to worsen.Effective treatment should be discussed.

塞利尼索治疗PET-MF 1例报告并文献复习

目的探讨原发性血小板增多症继发骨髓纤维化(PET-MF)的临床特点及诊治方法。方法报告1例PET-MF病人,结合相关的文献复习,总结其临床特点及诊治经验。结果病人有原发性血小板增多症病史9年,期间给予羟基脲、干扰素、阿司匹林治疗,疾病进展至骨髓纤维化后,给予芦可替尼治疗一度有效,后病人血小板计数持续增高,出现剧烈骨痛,在原来方案基础上联合塞利尼索治疗,病人骨痛感消失、脾脏缩小,治疗效果明显。结论PET-MF病人疾病进展后会出现骨痛、发热,使用包括JAK2抑制剂芦可替尼在内的传统治疗方案效果不佳时,可考虑联合新药核输出蛋白1抑制剂塞利尼索控制疾病进展及缓解病人症状。

An exceptional case of myelodysplastic syndrome with myelofibrosis following combination chemotherapy for squamous cell lung cancer

A 60-year-old woman with squamous cell carcinoma in the right lung was successfully treated with four cycles of combination chemotherapy after surgery, and complete remission was achieved. However, the patient developed myelodysplastic syndrome (MDS) RAEB-2 with myelofibrosis after remission, possibly because of chemotherapy or DNA methylation. The patient responded well to dacitabine (Dacogen), suggesting that DNA hypomethylation agents can be a promising therapy to retard the progression of a second tumor or carcinoma.